Analgesia can be produced by opioids microinjected intracerebroventricularly (ICV) or intrathecally (IT). Thus both spinal (IT) and supraspinal (ICV) brain sites contain opioid sensitive structures mediating analgesia. Recent studies indicate that morphine and other opioids produce analgesia in part through an indirect mechanism involving the activation of intrinsic descending pain inhibitory systems. Beta-Endorphin and morphine elicit their analgesic actions via the activation of different neuronal mechanisms as the blockade of spinal opioid receptors by naloxone or beta-FNA antagonizes ICV beta-endorphin- but not morphine-induced analgesia and ICV beta-endorphin but not morphine releases Met-enkephalin from the spinal cord. A model working hypothesis for the analgesic actions of beta-endorphin and morphine is proposed. The hypothesis is that the descending systems can be divided into two systems, an epsilon opioid receptor mediated and a mu-opioid receptor mediated descending system. The epsilon system is activated by beta-endorphin supraspinally and is mediated by a spinal enkephalinergic pathway. The mu system is activated by supraspinal morphine and is mediated by spinopetal monoaminergic pathways. The proposed studies are intended to characterize these two systems. The experiments include: a) mapping of the brain sites sensitive to beta-endorphin-induced spinal release of Met-enkephalin and -endorphin- and morphine- induced analgesia, b) the effects of ICV beta-endorphin and morphine on the spinal release of opioid peptides, c) the effects of ICV beta-endorphin and morphine on the in vivo opioid receptor binding in the spinal cord using tritiated diprenorphine, naloxone and etorphine as receptor binding ligands, d) the effects of he IT and ICV opioid antagonists on ICV beta-endorphin- and morphine- induced analgesia, e) the effects of development of spinal and supraspinal tolerance to selective opioid receptors on the ICV beta-endorphin- and morphine-induced analgesia, f) the effects of ICV morphine and beta-endorphin on spinal release of norepinephrine and serotonin and in vivo alpha-adrenergic receptor binding in the spinal cord, and g) the effects of IT biogenic amine antagonists and depletors on ICV beta-endorphin- and morphine-induced analgesia. A spinal perfusion technique will be used for studying the spinal release f opioid peptides and biogenic amines from the spinal cord. The opioid peptides will analyzed by radioimmunoassay.